We have found that 4-0-methylation of dopamine occurs in brain of man. The amount of 4-0-methyl dopamine found in the caudatenucleus of man (6 cases) ranged from 0-0.1 microgram/gram wet weight tissue. Also, a trace amount of iso-homovanillic acid (iso-HVA), the main acid metabolite of 4-0-methyl dopamine, was found in some of the human specimens which had 4-0-methyl dopamine. Also, in several animal species, i.e. rat, rabbit, and monkey, a small amount of 4-0-methyl dopamine was found in the basal ganglia. Upon the administration of 4-0-methyl DOPA I.P. to rats, a direct precursor of 4-0-methyl dopamine, large amounts of 4-0-methyl dopamine and iso-HVA were found in the brain. We propose to complete our studies with 4-0-methyl DOPA in rats. We plan to study also the metabolic fate of 4-0-methyl dihydroxyphenylserine (4-0-methyl DOPS) in rat brain, following the same approach. We will measure the presence of 4-0-methyl norepinephrine in rat brain, and its metabolites, i.e. 4-methoxy-3-hydroxyphenylglycol (iso-MHPG) and 4-methoxy-3-hydroxymandelic acid (iso-VMA). Our other goal is to look for 4-0-methyl metabolites of dopamine (4-0-methyl dopamine, iso-HVA) and norepinephrine (4-0-methyl norepinephrine, iso-MHPG, iso-VMA) in discrete regions of human brain obtained at post-mortem and in cerebrospinal fluid of patients with mental and neurological disorders, such as schizophrenia, manic-depressive reaction, Parkinson's disease (patients on and off L-DOPA). Highly sensitive and specific methods to separate and quantitate these compounds are available in our laboratories. These methods include column chromatography, organic solvent extractikn, gas chromatography with electron capture device, and mass spectrometry when needed. These studies will contribute to the furtherance of our knowledge related to the methylation of biogenic amines in brain and may provide a clue to the pathophysiology of some mental and neurologic disorders.